Most neuropsychiatric disorders have developmental origins. Such developmental vulnerability is often restricted to sensitive periods, but affected behaviors, modulating factors, and underlying mechanisms are scarcely understood. This grant aims at furthering our knowledge of sensitive periods that determine the developmental trajectory of complex behaviors, which is a necessary step towards improving prevention and treatment approaches for neuropsychiatric disorders. We have recently identified 2 sensitive developmental periods whereupon early-life perturbation of monoamine signaling alters adult behavior: an early postnatal (P2-P11) 5-HT-sensitive period that affects anxiety and depression-related behaviors and a later peri-adolescent (P22-P41) DA- and 5-HT-sensitive period altering aggression and behavioral response amphetamine (AMPH). Here we will focus on the study of the latter, peri-adolescent (PA) period. To that end, we designed a research plan to investigate the overarching hypothesis that peri- adolescent DAT and 5-HTT blockade have opposing effects on the maturation of the DA-system, predisposing or protecting against high aggression and dopamine dysfunction. Our application consists of three aims. In Aim1 we will more precisely define the temporal aspects of the PA sensitive period and broaden the analysis of behaviors impacted by PA 5-HTT- and DAT-inhibition. Results will guide experiments in Aim2 and Aim3 and will narrow down the potential developmental processes and circuits affected. Results will also help to translate findings across species, including humans. In Aim2 we will directly assess the impact of PA DAT- and 5-HTT-blockade on the function of the DA-system by investigating DAergic neuron activity in vitro and in vivo. Results will give us mechanistic insigh into which elements of the DA-system are altered, allowing us to devise rescue and causality-testing experiments. In Aim 3 we will investigate 5-HT/DA-interaction during and after PA DAT- and 5-HTT-inhibition. Results will shed light on how DAergic and 5-HTergic manipulations during PA development exert their opposing effects on circuit maturation and whether they permanently alter 5-HT/DA-interaction. Our research will impact the understanding of human risk factors for aggression and neuropsychiatric disorders with DA dysfunction. Our preliminary data suggest that genetic or environmental factors, which either increase DA signaling (such as stimulant use) or decrease 5-HT signaling during PA development act as risk factors for aggression and DA dysfunction. Conversely, genetic or environmental factors, which either decrease DA signaling or increase 5-HT signaling (such as SSRIs) during PA development, would act to ameliorate risk for aggression and DA dysfunction. Together with the mechanistic insight we will provide, our data could lead to improved diagnosis, prevention and treatment strategies in psychiatry.